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WO2011004017A1 - Composés 1-(azo-hétérocycle à 6 chaînons)-pyrrolin-2-one comme inhibiteurs de polymérase ns5b d'hépatite c, leur composition pharmaceutique et leur utilisation thérapeutique - Google Patents

Composés 1-(azo-hétérocycle à 6 chaînons)-pyrrolin-2-one comme inhibiteurs de polymérase ns5b d'hépatite c, leur composition pharmaceutique et leur utilisation thérapeutique Download PDF

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WO2011004017A1
WO2011004017A1 PCT/EP2010/059917 EP2010059917W WO2011004017A1 WO 2011004017 A1 WO2011004017 A1 WO 2011004017A1 EP 2010059917 W EP2010059917 W EP 2010059917W WO 2011004017 A1 WO2011004017 A1 WO 2011004017A1
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group
atom
phenyl
alkyl
optionally substituted
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Amaya Berecibar
Philippe Guedat
Céline MOHAMED-ARAB
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Vivalis SA
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Vivalis SA
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Priority to CA2767467A priority Critical patent/CA2767467A1/fr
Priority to JP2012519015A priority patent/JP2012532849A/ja
Priority to AU2010270152A priority patent/AU2010270152A1/en
Priority to EP10731522A priority patent/EP2451800A1/fr
Priority to US13/383,120 priority patent/US20120128630A1/en
Publication of WO2011004017A1 publication Critical patent/WO2011004017A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention concerns antiviral compounds, in particular anti hepatitis C compounds.
  • Viral proteins constitute a group of biologically active proteins with high pharmacological value. Drugs to deal with viral infections are a field of medicine that has been traditionally weak. However since the 1980s, the full genetic sequences of viruses began to be available to researchers, and they began to learn how viruses worked in detail, and to envision what kind of molecules were needed to jam their machinery. The general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be disabled. The targets should also be common across many strains of a virus, or even among different species of virus in the same family, so a single drug will have broad effectiveness. Dozens of "antiviral" treatments are now available, and a lot are currently under development. Most of the antivirals now available are designed to help deal with HIV, herpes virus, hepatitis B and C viruses and influenza viruses.
  • Viral life cycles vary in their precise details depending on the species of virus, but they all share a general pattern:
  • One of the major antivirals development approach is to interfere with the ability of a virus to get into a target cell.
  • the virus has to take a sequence of actions to do this, beginning with binding to a specific receptor molecule on the surface of the host cell and ending with the virus "un-coating" inside the cell and releasing its payload.
  • Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell, before they can uncoated. All these steps involve the binding of viral proteins with one or more binding partners. Indeed, a number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV.
  • Amantine and rimantadine are two entry-blockers that have been developed to combat influenza virus. Amantine and rimantadine are thought to interfere with influenza A virus M2 protein, an ion channel protein, and to inhibit virus uncoating. However, Amantine and rimantadine does not work on influenza B viruses and the two drugs have been associated with gastro-intestinal and central nervous system adverse effects. Pleconaril, another entry-blocker, works against rhinoviruses, which cause most colds, by blocking a pocket on the surface of the virus that controls the un-coating process. This pocket is similar in most strains of rhinoviruses, and the drug also seems to work against "entero-virus", which can cause diarrhea, meningitis, conjunctivitis, and encephalitis.
  • a second approach is to target the processes that synthesize virus components after a virus invades a cell.
  • Nucleotide or nucleoside analogues are antivirals that will interfere and block the enzymes that synthesize the RNA or DNA once the analogue is incorporated.
  • the first successful antiviral, "acyclovir” is a nucleoside analogue, and is effective against herpes virus infections.
  • Another nucleoside analogue named “zidovudine” or “AZT” has been approved for treating HIV.
  • Another class of antivirals that has been proven effective is the viral proteases inhibitors. Viral proteases act through binding to a target protein. However, protease inhibitors may have odd side-effects, for example causing fat to build up in unusual places. Then there is a need for improved protease inhibitors.
  • the final stage in the life cycle of a virus is the release of completed viruses from the host cell, and of course this step has also been targeted by antiviral drug developers.
  • Two drugs named "zanamivir” and “oseltamivir” that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named “neuraminidase” that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains. Those two drugs block the active site of the influenza viral enzyme neuraminidase.
  • Oseltamivir has been associated with adverse effects such as nausea and vomiting.
  • Zanamivir showed adverse respiratory events in persons with chronic pulmonary disease. Therefore there is a great need to extend the activity, the specificity and the efficacy of current antivirals, but also to extend the range of antivirals to other families of pathogens.
  • Hepatitis C is a global health problem with 170 million carriers' worldwide, 3 to 4 million new cases each year and a worldwide mortality estimated to 500,000 persons a year. 30% of liver grafts are currently prescribed to patients infected with HCV. HCV is spread primarily by direct contact with human blood. Transmission through blood transfusions that are not screened for HCV infection, through the re-use of inadequately sterilized needles and syringes or other medical equipment or through needle- sharing among drug users, is well documented. Sexual and perinatal transmission may also occur, although less frequently.
  • the incubation period of HCV infection before the onset of clinical symptoms ranges from 15 to 150 days. About 80 % of infected patients progress to develop chronic infection which can also be asymptomatic. Cirrhosis develops in about 10% to 20% of persons with chronic infection and liver cancer develops in 1% to 5% of persons with chronic infection over a period of 20 to 30 years.
  • Hepatitis C virus is an enveloped virus from the Flaviviridae family and is the only member of hepacivirus genus. HCV comprises 6 genotypes, more than 45 subtypes and quasi-species patient-specific. Its positive single strand linear RNA has about 9,600 nucleotides. RNA genome is flanked by two untranslated regions (UTR) that play a major role in translation and replication of the viral genome. Upon interaction and fusion of viral and cellular membranes, RNA genome is released into the cytoplasm of a newly infected cell and serves as template for RNA replication.
  • UTR untranslated regions
  • Viral genome replication is a two step process: the positive RNA strand is used as a matrix for the synthesis of a negative polarity RNA which in turn serves as matrix for the synthesis of positive RNA strands that will be incorporated in new virions.
  • Translation of HCV genome depends on an internal ribosome entry site and produces a large polyprotein which is proteolytically cleaved by cellular and viral proteases to produce 10 viral proteins.
  • the amino terminal one third of the polyprotein encodes the structural proteins: core protein glycoproteins El + E2. After the structural region, comes a small integral protein, P7, which seems to function as an ion chemical.
  • Replication complex is associated with membranes of the endoplasmic reticulum.
  • Viral proteins involved in this complex are the NTPase/helicase/serine protease NS3-4A, NS4B which is involved in the formation of the replication web, NS5A whose function still remains to be elucidated and the RNA-dependent RNA polymerase NS5B.
  • No vaccine is currently available to prevent hepatitis C.
  • the standard treatment consists in a combination between Interferon, a cytokine with immuno-modulatory and antiviral activity (Moussalli et al, 1998) and Ribavirin, a synthetic guanosine nucleoside analogue (Hugle et al., 2003).
  • the sustained viral response Loss of serum HCV RNA following 24 weeks of antiviral therapy is at best 42-46% (Walker et al. 2002, Gordon et al., 2005; Lake-Bakaar et al., 2003).
  • NS5B RNA polymerase is a 66 kD oligomeric, tail-anchored protein (Ivashkina et al., 2002; Schmidt-Mende et al., 2001). Its C-terminal 21 residues form an ⁇ -helical transmembrane domain responsible for post-translational targeting to the cytosolic side of the ER, where the functional protein domain is exposed (Moradpour et al., 2004; Schmidt-Mende et al., 2001).
  • NS5B The crystal structure of NS5B revealed that the RdRp has a classical "fingers, palm and thumb” structure (Ago et al., 1999; Bressanelli et al., 1999; Lesburg et al., 1999). Unlike many cellular and other viral polymerase, interactions between the fingers and thumb subdomains result in a completely encircled catalytic site that ensures synthesis of positive- and negative- strand HCV RNAs (Lesburg et al., 1999). A unique feature is the presence of a B- harpin in the thumb subdomain that protrudes toward the active site and may thus restrict binding of the template/primer at the active site. NS5B catalyzes de novo, primer-independent initiation of RNA synthesis followed by elongation, termination of polymerization and release of nascent strand.
  • the present invention concerns a compound of the following formula I or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof:
  • Y represents an oxygen atom or a sulfur atom, advantageously an oxygen atom
  • Z represents an oxygen atom, a -CH-R group or a -N-OR group, in which R represents an hydrogen atom, a Ci-C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a 5-6 members heterocyclic group containing one or two heteroatoms selected in the group consisting of oxygen, nitrogen and sulfur atom, a (Ci-C 6 alkyl)COOH group, a (C 1 - C 6 alkyl)O(Ci-C 6 alkyl) group or a O-protecting group; advantageously Z represents an oxygen atom or a -N-OR group in which R represent a Ci-C 6 alkyl group, a (C 1 - C 6 alkyl)O(Ci-C 6 alkyl) group or a (Ci-C 6 alkyl)COOH group; in particular R represents a CH 2 -CH 2 -OMe group or a methyl group.
  • Z represents an oxygen atom.
  • Rl represents a phenyl group or a 5- or 6-members heteroaryl group containing one, two or three heteroatoms selected in the group consisting of oxygen, nitrogen and sulfur atom, advantageously nitrogen and sulfur atom, in particular a thiazol a thiadiazol or pyridine group, the phenyl group and the heteroaryl group being optionally substituted, in particular at the para position for the phenyl and the 6- members heteroaryl group, by a halogen atom; a -CN group; a -S ⁇ 2-(Ci-Ce) alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a phenyl group; a 5- or 6-members heteroaryl group containing one, two or three heteroatoms selected in the group consisting of oxygen, nitrogen and sulfur atom, advantageously a nitrogen atom; a Ci-C 6 alkyl group optionally
  • the phenyl or the heteroaryl group is substituted, more particularly at the para position for the phenyl and the 6-members heteroaryl group, by a halogen atom; a phenyl group; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a O-(Ci-C 6 )alkyl-O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a - O-(Ci-C 6 )alkyl-phenyl-
  • the phenyl or the heteroaryl group is substituted, more particularly at the para position for the phenyl and the 6-members heteroaryl group, by a C 2 -C 6 alkenyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; or a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, in particular a Ci-C 6 alkyl group.
  • the phenyl or the heteroaryl group is substituted, more particularly at the para position for the phenyl and the 6-members heteroaryl group, by a Ci-C 6 alkyl group, in particular a methyl, ethyl, tert-butyl, isobutyl or isopropyl group, optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 2 -C 6 alkenyl group, in particular a isopropenyl group; a -0-(Ci-C 6 ) alkyl group, in particular a O-methyl group, in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom.
  • a Ci-C 6 alkyl group in particular a methyl, ethyl, tert-butyl, isobutyl or isopropyl group, optionally substituted by one or more halogen atom, in particular
  • the phenyl or the heteroaryl group is substituted, more particularly at the para position for the phenyl and the 6-members heteroaryl group, by a Ci-C 6 alkyl group, in particular a methyl or isopropyl group, or a -OCF 3 group, or a -CF 3 group.
  • R2 represents a phenyl group, or a 5- or 6-members heteroaryl group containing one two or three heteroatom(s) selected in the group consisting of oxygen, sulfur and nitrogen atom, advantageously nitrogen and sulfur atom, in particular a thiazol a thiadiazol or pyridine group the phenyl group and the heteroaryl group being optionally substituted by one or more groups, advantageously one or two groups, independently selected among a halogen atom; a -OH group; a -CN group; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom, or by a 5-members heteroaryl group containing one, two, three or four heteroatom (s) selected in the group consisting of oxygen, sulfur and nitrogen atom, advantageously nitrogen atom;
  • the phenyl or the heteroaryl group is substituted by a halogen atom; a -OH group; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a phenyl group; a -O-phenyl group; a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group; a -O-(6- members heterocyclic) group in which the heterocyclic group contains one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom, advantageously nitrogen atom;
  • the phenyl or the heteroaryl group is substituted by a -O-(5-members heteroaryl) group in which the heteroaryl group contains one, two, three or four heteroatom (s), in particular three heteroatoms, selected in the group consisting of oxygen, sulfur and nitrogen atom, advantageously nitrogen atom, the heteroaryl group being optionally substituted by a -(Ci-C 6 alkyl)-phenyl group, a -(Ci-C 6 alkyl) group or a -CH 2 -O-CH 2 -Si(CHs) 3 group, the alkyl group being optionally substituted by a halogen atom, advantageously the heteroaryl group is substituted by a -CH 2 -O- CH 2 -Si(CH 3 ) 3 group; a halogen atom; a -S-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular
  • the phenyl or heteroaryl group is substituted by a halogen atom, in particular a boron atom; a -S-(Ci-C 6 )alkyl group in particular a -SCH(CHs) 2 ; a C 2 -C 6 alkenyl group, in particular a isopropenyl group; a -O-(C 3 -C 6 )cycloalkyl group in particular a -O-cyclopropyl; a Ci-C 6 alkyl group, in particular a tert-butyl group, an ethyl group or a isopropyl group, optionally substituted by one or more halogen atom, more particularly a -CF 3 group or a - CF 2 CH 3 group, a -O-(Ci-C 6 )alkyl group, in particular a O-methyl, O-ethyl or a O- isopropyl group, in which the alkyl
  • the phenyl or the heteroaryl group is substituted by a Ci-C 6 alkyl group, in particular a isopropyl group, optionally substituted by one or more halogen atom, more particularly a -CF 3 group or a -CF 2 CH 3 group; or a -0-(Ci-C 6 ) alkyl group, in particular a O-methyl, in which the alkyl group is optionally substituted by one or more halogen atom, in particular a -OCF 3 group.
  • the phenyl or the heteroaryl group is substituted by -CF 3 or a -CF 2 CH 3 group; -OCF 3 or an isopropyl group.
  • R3 represents a 6-members heteroaryl group containing as the only heteroatom(s), one, two or three nitrogen atoms, advantageously two or three nitrogen atoms, the heteroaryl group being optionally substituted by a halogen atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom, by a -O-(Ci-C 6 )alkyl group, by a -0-C 3 -C 6 cycloalkyl group, by a -O-aryl group or by a -NR' R" group in which R' and R" represent independently of each other a hydrogen atom, a Ci-C 6 alkyl group, a C 3 -C 6 cycloalkyl group or an aryl group; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(C
  • heteroaryl group which is optionally substituted by a Ci-C 6 alkyl group optionally substituted by a -O-(Ci-C 6 )alkyl group, by a -O-C3-C6 cycloalkyl group, by a -O-aryl group or by a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom, a Ci-C 6 alkyl group, a C 3 -C 6 cycloalkyl group or an aryl group, contains as the only heteroatom(s), two or three nitrogen atoms.
  • the heteroaryl group is unsubstituted or substituted by a halogen atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a -COOH group; a -COO(C i-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom in particular a fluorine atom; a -CN group; a -SO2-phenyl-NO2 group; a -S ⁇ 2-(Ci-C 6 )alkyl group; a -S ⁇ 2-
  • the heteroaryl group is unsubstituted or substituted by a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, more particularly a fluorine atom; a halogen atom, in particular a chlorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by a phenyl group, in particular - OCH 3 group or a-OCH 2 phenyl group; a -OH group; a -S-phenyl-N ⁇ 2 group; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, more particularly a fluorine atom; a -CN group; or a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, advantageously a Ci-C 6 alkyl group.
  • the heteroaryl group is unsubstituted or substituted by a Ci-C 6 alkyl group, in particular a methyl group, or a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, advantageously a Ci-C 6 alkyl group.
  • the heteroaryl group is substituted by a Ci-C 6 alkyl group, in particular a methyl group
  • the compounds of formula (a), (b), (c) and (d) are known as such but they have never been described as having a therapeutic activity, in particular an antiviral activity, more particularly an anti HCV activity.
  • the compound of formula I does not correspond to the
  • the compounds of formula (g), (u) and (v) are known as such but they have never been described as having a therapeutic activity, in particular an antiviral activity, more particularly an anti HCV activity.
  • R3 represents a group of the following formula II : R 7 (II) in which X represents a nitrogen atom and Y represents a -C-R8 group, or X represents a -C-R9 group and Y represents a nitrogen atom, or X represents a -C-R9 group and Y represents a -C-R8 group, advantageously X represents a -C-R9 group and Y represents a -C-R8 group; R7, R8 and R9 represent independently of each other a hydrogen atom; a halogen atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom, by a -O-(Ci-C 6 )alkyl group, by a -O-C3-C6 cycloalkyl group, by a -O-aryl group or by a -NR'
  • R7, R8 and R9 represent independently of each other a hydrogen atom; a halogen atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a -COOH group; a -COO(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom in particular a fluorine atom; a -CN group; a -SCVphenyl-NC ⁇ group; a -S ⁇ 2-(Ci-Ce)alkyl group; a -SC
  • R7, R8 and R9 represent independently of each other a hydrogen atom; a halogen atom, in particular a chlorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by a phenyl group, in particular - OCH3 group or a-OC ⁇ bphenyl group; a -OH group; a -S-phenyl-NCh group; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; or a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, advantageously a Ci-C 6 alkyl group.
  • R7, R8 and R9 represent independently of each other a hydrogen atom; a Ci-C 6 alkyl group, in particular a methyl group, or a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, advantageously a Ci-C 6 alkyl group. Still more advantageously R8 and R9 represent a hydrogen atom. Even still more advantageously, R7 represents a Ci-C 6 alkyl group, in particular a methyl group.
  • the compound according to the present invention or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof is such that R3 represents a 6-members heteroaryl group containing as the only heteroatom, one nitrogen atom, advantageously a pyridyl group, said heteroaryl group being optionally substituted by a halogen atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom, or by a phenyl group; a -OH group; a -COOH group;
  • the heteroaryl group is unsubstituted or substituted by a halogen atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a -COOH group; a -COO(C i-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom in particular a fluorine atom; a -CN group; a -SO2-phenyl-NO2 group; a -S ⁇ 2-(Ci-C 6 )alkyl group; a -S ⁇ 2-
  • the heteroaryl group is unsubstituted or substituted by a halogen atom, in particular a chlorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by a phenyl group, in particular -OCH 3 group or a- OCH 2 phenyl group; a -OH group; a -S-phenyl-N ⁇ 2 group; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, more particularly a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, more particularly a fluorine atom; a -CN group; or a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, advantageously a Ci-C 6 alkyl group.
  • the heteroaryl group is unsubstituted or substituted by a Ci-C 6 alkyl group, in particular a methyl group, or a -CN group. Even still more advantageously, the heteroaryl group is substituted by a Ci-C 6 alkyl group, in particular a methyl group.
  • the compound according to the present invention or a salt, solvate, tautomer, isotope enantiomer, diastereoisomer or racemic mixture thereof is such that R2 represents a phenyl group or a pyridyl group, in particular a phenyl group, optionally substituted by one or more groups, advantageously one group, more advantageously at the para position, independently selected among a halogen atom; a -OH group; a -CN group; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom, or by a 5 -members heteroaryl group containing one, two, three or four heteroatom (s) selected in the group consisting of oxygen, sulfur and nitrogen atom, advantageously nitrogen atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a
  • the phenyl or pyridyl group is substituted by a halogen atom; a -OH group; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom in particular a fluorine atom; a phenyl group; a -O-phenyl group; a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, a -0-(6-members heterocyclic) group in which the heterocyclic group contains one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and
  • the phenyl or pyridyl group is substituted by a -O-(5 -members heteroaryl) group in which the heteroaryl group contains one, two, three or four heteroatom (s), in particular three heteroatoms, selected in the group consisting of oxygen, sulfur and nitrogen atom, advantageously nitrogen atom, the heteroaryl group being optionally substituted by a -(Ci-C 6 alkyl)-phenyl group, a -(Ci-C 6 alkyl) group or a -CH 2 -O-CH 2 -Si(CHs) S group, the alkyl group being optionally substituted by a halogen atom, advantageously the heteroaryl group is substituted by a -CH 2 -O- CH 2 -Si(CHs) 3 group; a halogen atom; a -S-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom,
  • the phenyl or pyridyl group is substituted by a halogen atom, in particular a boron atom; a -S-(Ci-C 6 )alkyl group in particular a -SCH(CHs) 2 ; a C 2 -C 6 alkenyl group, in particular a isopropenyl group; a -O-(C 3 -C 6 )cycloalkyl group in particular a -O-cyclopropyl; a Ci-C 6 alkyl group, in particular a tert-butyl group, an ethyl group or a isopropyl group, optionally substituted by one or more halogen atom, more particularly a -CF 3 group or a - CF 2 CH 3 group, a -O-(Ci-C 6 )alkyl group, in particular a O-methyl, O-ethyl or a O- isopropyl group, in which the
  • the phenyl or pyridyl group is substituted by a Ci-C 6 alkyl group, in particular a isopropyl group, optionally substituted by one or more halogen atom, more particularly a -CF 3 group or a -CF 2 CH 3 group; or a -O-(Ci-C 6 )alkyl group, in particular a O-methyl, in which the alkyl group is optionally substituted by one or more halogen atom, in particular a -OCF 3 group.
  • the phenyl or pyridyl group is substituted by -CF 3 ; -OCF 3 , -CF 2 CH 3 or an isopropyl group.
  • the compound according to the present invention or a salt, solvate, tautomer, isotope enantiomer, diastereoisomer or racemic mixture thereof is such that Rl represents a phenyl or pyridyl group, in particular a phenyl group, optionally substituted, advantageously at the para position, by a halogen atom; a -CN group; a -S ⁇ 2-(Ci-Ce) alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 2 -C 6 alkenyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen
  • the phenyl or pyridyl group is substituted, more particularly at the para position, by a halogen atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a - O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom in particular a fluorine atom; a O-(Ci-C 6 )alkyl-O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a phenyl group; ; a -O-(Ci-C 6 )alkyl-phenyl-O-(Ci-C 6 )alkyl group
  • the phenyl or pyridyl group is substituted, more particularly at the para position, by a C 2 -C 6 alkenyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a Ci-C 6 alkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; a -O-(Ci-C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogen atom, in particular a fluorine atom; or a -NR'R" group in which R' and R" represent independently of each other a hydrogen atom or a Ci-C 6 alkyl group, in particular a Ci-C 6 alkyl group.
  • the phenyl or pyridyl group is substituted, more particularly at the para position, by a Ci-C 6 alkyl group, in particular a methyl, ethyl, tert-butyl, isobutyl or isopropyl group, optionally substituted by one or more halogen atom, in particular a fluorine atom; a C 2 -C 6 alkenyl group, in particular a isopropenyl group; a -O-(Ci-C 6 )alkyl group, in particular a O-methyl group, in which the alkyl group is optionally substituted by one or more halogen atom, in particular a fluorine atom.
  • the phenyl or pyridyl group is substituted, more particularly at the para position, by a C 1 - C 6 alkyl group in particular a methyl or isopropyl group, or a -OCF 3 group or a CF 3 group.
  • the compound according to the present invention a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof, is chosen from the group consisting of the compounds of the following formula 1, 3-10, 14-64, 66, 67, 74-80, 82-106 and 108-212.
  • the particularly advantageous compounds are enantiomers of the compounds according to the present invention having the following formula:
  • Rl, R2, R3, R4, Y, Z and n are as defined above.
  • the compounds according to the present invention can be prepared by methods well known in the art. In particular they can be prepared by the general procedure A, C, D, E, G, H, or J as described bellow.
  • the present invention also concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof and pharmaceutically acceptable excipients.
  • the pharmaceutical composition according to the present invention contains a further antiviral agent, in particular selected in the group consisting of ribavirin, interferon, inhibitors of HCV helicase, inhibitors of HCV protease, inhibitors of HCV NS4A, inhibitors of HCV NS5B, inhibitors of HCV NS5A, anti- HIV agent and mixture thereof.
  • a further antiviral agent in particular selected in the group consisting of ribavirin, interferon, inhibitors of HCV helicase, inhibitors of HCV protease, inhibitors of HCV NS4A, inhibitors of HCV NS5B, inhibitors of HCV NS5A, anti- HIV agent and mixture thereof.
  • the present invention concerns also a composition according to the present invention, a compound according to the present invention, or a compound of formula (a), (b), (c) or (d) as defined above or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof for use as a drug, in particular as an antiviral drug, advantageously intended to treat hepatitis, in particular hepatitis C, for example as a hepatitis C polymerase inhibitor.
  • the present invention also concerns a product containing a compound according to the present invention or a compound of formula (a), (b), (c) or (d) as defined above or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof and at least another antiviral agent, in particular selected in the group consisting of ribavirin, interferon, inhibitors of HCV helicase, inhibitors of HCV protease, inhibitors of HCV NS4A, inhibitors of HCV NS5B, inhibitors of HCV NS5A, inhibitors of HCV polymerase, anti-HIV agent and mixture thereof, as a combined preparation for simultaneous, separate or sequential use in hepatitis therapy, in particular in patients having the HIV disease.
  • antiviral agent in particular selected in the group consisting of ribavirin, interferon, inhibitors of HCV helicase, inhibitors of HCV protease, inhibitors of HCV NS4A
  • the compound according to the present invention can be used as a bi- or tri-therapy in order to treat hepatitis C with another anti-hepatitis C antiviral agent (ribavirin, interferon, inhibitors of HCV helicase, inhibitors of HCV protease, inhibitors of HCV NS4A, inhibitors of HCV NS5B, inhibitors of HCV NS5A, inhibitors of HCV polymerase or mixture thereof) or even as a bi or tri-therapy with one or several anti-HIV antiviral agent in order to treat hepatitis C in a patient having HIV disease or finally as a tri-therapy with another anti-hepatitis C antiviral agent and an anti-HIV antiviral agent in order to treat hepatitis C in a patient having HIV disease.
  • another anti-hepatitis C antiviral agent ribavirin, interferon, inhibitors of HCV helicase, inhibitors of HCV protease, inhibitors of HCV NS4A,
  • antiviral agent any of several drugs used to treat or prevent viral infections.
  • the drugs act by interfering with a virus's ability to enter a host cell and replicate itself with the host cell's DNA. Some drugs block the virus's attachment or entry into the cell; others inhibit replication or prevent the virus from shedding the protein coat that surrounds the viral DNA.
  • Antiviral agents or drugs are now available for a wide variety of viral diseases.
  • Ribavirin available since the mid-1980s, is used to treat respiratory syncytial virus (RSV), a cause of severe childhood respiratory infections. It is thought to inhibit messenger RNA. Amantadine and rimantadine, which are effective against strains of influenza A, act by interfering with viral uncoating.
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stochiometric amount of the desired salt-forming acid or base.
  • Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases.
  • Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine.
  • Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids.
  • Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulphate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulphate, sulphosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide. Hydrochloride salts are particularly preferred.
  • the compounds of the invention can be administered by oral or parenteral routes, intestinal, ocular, vaginal, rectal nasal (intranasal), pulmonary or other mucosal, transdermal and topical administration, and inhalation, advantageously by oral route.
  • Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration.
  • Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration.
  • the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose.
  • Corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • compositions of the present invention may, in particular, comprise more than one agent (multiple) of the present invention, e.g., two or more agents.
  • the invention also provides a pharmaceutical preparation or system, comprising (a) a first agent, which is an agent of the invention; and (b) a second pharmaceutical agent. Said multiple agents of the invention or said first and second agents are formulated either in admixture or as separate compositions, e.g. for simultaneous though separate, or for sequential administration (see below).
  • compositions of the present invention can be delivered directly or in pharmaceutical compositions containing excipients (see above), as is well known in the art.
  • the present methods of treatment involve administration of a therapeutically effective amount of an agent of the present invention to a subject.
  • therapeutically effective amount refers to an amount of an agent according to the present invention needed to treat or ameliorate the targeted disease condition, or to exhibit a detectable therapeutic effect or a prolongation of survival in a patient.
  • the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, for example, in non-human primates, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration.
  • Effective doses of the compounds of the present invention may be ascertained by conventional methods.
  • the specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration, the general health of the patient (i.e. age, weight and diet) in particular if he is a HIV patient, the gender of the patient, the time and frequency of administration, and tolerance/response to therapy.
  • the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 2500 mg per day, and most usually from 10 to 1500 mg per day.
  • dosages can be administered per unit body weight and in this instance a typical dose will be between 0.01 ⁇ g/kg and 50 mg/kg, especially between 10 ⁇ g/kg and 10 mg/kg, between 100 ⁇ g/kg and 2 mg/kg.
  • An advantage of the compounds of the present invention is that they permit administration to be limited to one, two, three or four times weekly or monthly.
  • compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass and rubber stoppers such as in vials.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising an agent of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition.
  • compositions “comprising” X may consist exclusively of X or may include something additional e.g. X + Y.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centres, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all such isomers and mixtures thereof in all proportion are encompassed within the scope of the present invention.
  • substituted for example a phenyl group comprising a substituent on the aryl ring, unless specified otherwise, the term "substituted" contemplates all possible isomeric forms.
  • substituted phenyl includes all of the following ortho-, meta- and para- permutations: However, in general para substitution is preferred.
  • tautomer » refers to isomers of the compounds according to the present invention that readily interconvert by a chemical reaction called tautomerization. Commonly this reaction results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.
  • Common tautomeric pairs are: ketone - enol; amide - imidic acid; lactam - lactim, an amide - imidic acid tautomerism in heterocyclic rings; enamine - imine; enamine - enamine.
  • it can include ring-chain tautomerism which occurs when the movement of the proton is accompanied by a change from an open structure to a ring.
  • isotope » refers to two molecules which differ only in the isotopic nature of their atoms i.e. their atom have a different atomic mass (mass number). Isotopes of an atom have nuclei with the same number of protons (the same atomic number) but different numbers of neutrons. Therefore, isotopes have different mass numbers, which give the total number of nucleons, the number of protons plus neutrons.
  • an isotope of a compound can comprise one deuterium atom in place of a hydrogen atom.
  • halogen is used herein to refer to any of fluorine, chlorine, bromine and iodine. Most usually, however, halogen substituents in the compounds of the invention are chlorine, bromine and fluorine substituents, in particular fluorine substituents.
  • O-Protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures.
  • O-protecting groups comprise substituted methyl ethers, for example, methoxymethyl (MOM), benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl, tetrahydropyranyl ethers, substituted ethyl ethers, for example, 2,2,2-trichloroethyl, silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl (TBS) and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid for example, acetate, propionate, benzoate and the like.
  • an allyl or an acetyl group is an "O-Protecting
  • alkyl refers to a straight or branched saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated.
  • Ci-C 6 -alkyl includes C 1 , C 2 , C 3 , C 4 , Cs and C 6 alkyl groups.
  • suitable alkyl groups include methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • alkyl groups are: Ci-C 6 -alkyl, Ci-Cs-alkyl, Ci-C4-alkyl, Ci-C3-alkyl and Ci-C 2 -alkyl, in particular Ci-C 3 -alkyl.
  • alkenyl refers to a straight or branched monovalent hydrocarbon radical, having the number of carbon atoms as indicated and at least a double bond.
  • C2-C6-alkenyl includes C 2 , C 3 , C 4 , Cs and C 6 alkenyl groups.
  • suitable alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, iso-butenyl, tert-butenyl, pentenyl and hexenyl.
  • alkenyl groups are: C 2 -C 6 - alkenyl, C 2 -Cs-alkenyl, C 2 -C 4 -alkenyl and C 2 -C 3 -alkenyl in particular C 2 -C 4 -alkenyl.
  • alkynyl refers to a straight or branched monovalent hydrocarbon radical, having the number of carbon atoms as indicated and at least a triple bond.
  • C 2 -C6-alkynyl includes C 2 , C 3 , C 4 , Cs and C 6 alkynyl groups.
  • suitable alkynyl groups include ethynyl, propynyl, iso-propynyl, butynyl, iso-butynyl, tert-butynyl, pentynyl and hexynyl.
  • ranges of alkynyl groups are: C 2 -C 6 - alkynyl, C 2 -Cs-alkynyl, C 2 -C 4 -alkynyl and C 2 -C 3 -alkynyl in particular C 2 -C 3 -alkynyl.
  • cycloalkyl refers to a cyclic saturated hydrocarbon radical, having the number of carbon atoms as indicated.
  • C 3 - C ⁇ -cycloalkyl includes C 3 , C 4 , Cs and C 6 cycloalkyl groups.
  • suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl and cyclopentylmethyl.
  • ranges of alkyl groups are: Cs-C ⁇ -cycloalkyl, Cs-Cs-cycloalkyl and C 3 -C 4 -cycloalkyl.
  • aryl refers to monovalent unsaturated aromatic carbocyclic radical having one, two, or three rings, which may be fused or bicyclic.
  • aryl refers to an aromatic monocyclic ring containing 5 or 6 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4 or 5 substituents as defined herein; an aromatic bicyclic or fused ring system containing 7, 8, 9 or 10 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents as defined herein; or an aromatic tricyclic ring system containing 10 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 substituents as defined herein.
  • suitable aryl groups include phenyl, biphenyl, indanyl, azulenyl, tetrahydronaphthyl, tolyl, chlorophenyl, dichlorophenyl, trichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, fluorophenyl, difluorophenyl, trifluorophenyl, nitrophenyl, dinitrophenyl, trinitrophenyl, aminophenyl, diaminophenyl, triaminophenyl, cyanophenyl, chloromethylphenyl, tolylphenyl, chloroethylphenyl, trichloromethylphenyl, dihydroindenyl, benzocycloheptyl and trifluoromethylphenyl, advantageously a phenyl.
  • aryl groups are: C 3 -io-aryl, C 3 - 6 -aryl C 4 - 9 -aryl, Cs- 8 -aryl and C 6 - 7 - aryl.
  • heteroaryl refers to monovalent unsaturated aromatic heterocyclic radicals having one ring.
  • the term “6-members heteroaryl” encompasses heteroaryl moieties that are aromatic monocyclic ring systems containing six members of which at least one member is a N, O or S atom and which optionally depending of the case can contain one, two or three additional N, O or S atoms, advantageously N atoms.
  • heteroaryl encompasses heteroaryl moieties that are aromatic monocyclic ring systems containing five members of which at least one member is a N, O or S atom and which optionally depending of the case can contain one, two or three additional N, O or S atoms, advantageously N atoms.
  • suitable heteroaryl groups include furanyl, pyridyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazinyl, oxazinyl, tetrazol, oxadiazol and triazol.
  • heterocyclic refers to a saturated or partially unsaturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one or two N atoms; a saturated or partially unsaturated ring having six members of which one, two or three members are an N,
  • heterocycles comprising peroxide groups are excluded from the definition of heterocyclic.
  • suitable heterocyclic groups include pyrrolinyl, pyrrolidinyl, dioxolanyl, tetrahydrofuranyl, morpholinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl and piperazinyl.
  • the reactants and commercials compounds were purchased from Acros Organics, Sigma-Aldrich, Alfa Aesar, Interchim and Maybridge.
  • Example 1 6-[2-(4-tert-butyl-phenyl)-4-hydroxy-3-(4-methyl-benzoyl)-5-oxo-2,5- dihydro-pyrrol-1-yl] -nicotinic acid methyl ester.
  • Example 2 5-(4-tert-butyl-phenyl)-3-hydroxy-4-(4-methyl-benzoyl)-l-pyridin-2-yl- l,5-dihydw-pyrwl-2-one.
  • Example 3 6-[3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-2-oxo-2,5- dihydro-pyrrol-1-yl] -nicotinic acid methyl ester.
  • Example 4 3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-pyrazin-2-yl- 1, 5-dihydro-pyrrol-2-one.
  • Example 5 6-[3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-2-oxo-2,5- dihydro-pyrrol-1-yl] -nicotinic acid.
  • Example 6 l-(5-chlow-pyridin-2-yl)-3-hydwxy-5-(4-isopwpyl-phenyl)-4-(4- methyl-benzoyl)-l,5-dihydro-pyrrol-2-one.
  • Example 7 6-[3-hydwxy-5-(4-isopwpyl-phenyl)-4-(4-methyl-benzoyl)-2-oxo-2,5- dihydw-pyrwl-1-ylJ-nicotinonitrile.
  • Example 8 3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 10 5-(4-tert-butyl-phenyl)-3-hydwxy-4-(4-methoxy-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 52 3-Hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-(6-methyl- pyridin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 14 l-(5-fluoro-pyridin-2-yl)-3-hydroxy-5-(4-isopropyl-phenyl)-4-(4- methyl-benzoyl)-l,5-dihydro-pyrrol-2-one.
  • Example 15 3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-(6- morpholin-4-yl-pyridazin-3-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 16 4-(3-chloro-benzoyl)-3-hydroxy-5-(4-isopropyl-phenyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 17 3-hydwxy-5-(4-isopwpyl-phenyl)-4-(3-methoxy-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 18 3-hydwxy-4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- tri ⁇ uoromethyl-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 19 3-hydroxy-5-(4-isopropyl-phenyl)-4-(2-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 21 3-hydwxy-5-(3-methoxy-phenyl)-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 22 3-hydroxy-4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 23 3-hydroxy-4-(4-methoxy-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 24 3-hydwxy-5-(4-methoxy-phenyl)-l-(6-methyl-pyridazin-3-yl)-4-(4- tri ⁇ uoromethoxy-benzoyl)-!, 5-dihydw-pyrwl-2-one. Prepared from/?-anisaldehyde, 3-amino-6-methylpyridazine and 2-hydroxy-4-oxo-4-
  • Example 25 3-hydroxy-5-(4-isopropyl-phenyl)-l-(6-methyl-pyridazin-3-yl)-4-(4- trifluoromethoxy-benzoyl)-l,5-dihydro-pyrrol-2-one.
  • Example 26 3-hydroxy-5-(4-methoxy-phenyl)-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 27 3-hydwxy-4-(4-methoxy-benzoyl)-5-(4-methoxy-phenyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 28 3-hydroxy-4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(3- tri ⁇ uoromethyl-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 29 3-hydroxy-5-(3-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 31 3-hydroxy-4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(3- pwpoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 32 4-(3-dimethylamino-benzoyl)-3-hydroxy-5-(4-isopropyl-phenyl)-l-(6- methyl-pyridazin-3-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 34 3-hydwxy-5-methyl-4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3- yl)-l, 5-dihydw-pyrwl-2-one.
  • Example 35 4-(4-dimethylamino-benzoyl)-3-hydroxy-5-(4-isopropyl-phenyl)-l-(6- methyl-pyridazin-3-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 36 3-hydroxy-5-(2-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 37 l-(6-dimethylamino-pyridazin-3-yl)-3-hydwxy-5-(4-isopwpyl- phenyl)-4-(4-methyl-benzoyl)-l, 5-dihydw-pyrwl-2-one.
  • Example 38 3-hydroxy-5-(3-isopropoxy-phenyl)-4-(4-methyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 40 3-hydwxy-5-(4-isopwpyl-phenyl)-4-(4-methyl-benzoyl)-l-[6-(4- methyl-piperazin-l-yl)-pyridazin-3-yl]-l,5-dihydw-pyrwl-2-one.
  • Example 41 3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-(5-methyl- pyridin-2-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 42 5-biphenyl-4-yl-3-hydroxy-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 44 3-hydroxy-4-(4-isopropyl-benzoyl)-5-(4-isopropyl-phenyl)-l-(5- methyl-pyridin-2-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 45 5-biphenyl-4-yl-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 48 3-hydroxy-4-(4-isopropyl-benzoyl)-5-(4-isopropyl-phenyl)-l-(6- methyl-pyridin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 50 3-hydwxy-4-(4-methyl-benzoyl)-5-[4-(l-methyl-piperidin-4-yloxy)- phenyl]-l-(6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 51 3-hydwxy-5-(4-methoxy-phenyl)-l-(6-methyl-pyridazin-3-yl)-4-(4- morpholin-4-yl-benzoyl)-l,5-dihydro-pyrrol-2-one.
  • Example 77 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 78 5- ⁇ 4-[4-(2-Dimethylamino-ethyl)-piperazin-l-yl]-phenyl ⁇ -3-hydwxy- 4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 80 3-hydwxy-l-(6-methyl-pyridazin-3-yl)-4-(4-morpholin-4-yl-benzoyl)- 5-(4-tri ⁇ uowmethoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 82 3-Hydroxy-4-[4-(4-methoxy-benzyloxy)-benzoyl]-l-(6-methyl- pyridazin-3-yl)-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 85 3-Hydroxy-4-[4-(2-methoxy-ethoxy)-benzoyl]-l-(6-methyl-pyridazin- 3-yl)-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 87 5-(4-chloro-phenyl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 57 5-(2,4-dimethyl-phenyl)-3-hydwxy-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 58 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- morpholin-4-yl-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 59 5-[4-(2-dimethylamino-ethoxy)-phenyl]-3-hydroxy-4-(4-methyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 60 3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)-l-(5- trifluoromethyl-pyridin-2-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 61 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 62 3-hydwxy-4-(4-isopwpyl-benzoyl)-5-(4-methoxy-phenyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one. Prepared from /?-anisaldehyde, 3-amino-6-methylpyridazine and 2-hydroxy-4-(4- isopropyl-phenyl)-4-oxo-but-2-enoic acid ethyl ester in 14% yield.
  • Example 63 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethyl-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 64 5- ⁇ 4-[4-(2-Dimethylamino-ethyl)-piperazin-l-yl]-phenyl ⁇ -3-hydroxy- 4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 89 3-hydroxy-5-(4-isopropoxy-phenyl)-4-(4-isopropyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 93 3-hydwxy-l-(6-methyl-pyridazin-3-yl)-4-(4-pyridin-2-yl-benzoyl)-5- (4-tri ⁇ uowmethoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 94 3-hydwxy-5-(4-isopwpyl-phenyl)-l-(6-methyl-pyridin-3-yl)-4-(4- tri ⁇ uoromethoxy-benzoyl)-l,5-dihydw-pyrwl-2-one.
  • Example 95 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-4-(4-trifluoromethyl-benzoyl)- 5-(4-trifluoromethyl-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 96 3-hydwxy-l-(6-methyl-pyridazin-3-yl)-4-(4-trifluowmethoxy- benzoyl)-5-(4-tri ⁇ uowmethoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 99 5-(4-difluowmethoxy-phenyl)-3-hydwxy-4-(4-methoxy-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 100 3-hydwxy-5-(4-isopwpoxy-phenyl)-4-(4-methoxy-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l, 5-dihydw-pyrwl-2-one.
  • Example 101 4-(4-ethoxy-benzoyl)-3-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 102 4-(4-ethyl-benzoyl)-3-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 103 3-hydwxy-l-(6-methyl-pyridazin-3-yl)-4-(pyridine-4-carbonyl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 104 5-(4-ethoxy-phenyl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 105 5-(4-ethyl-phenyl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 106 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(5- tri ⁇ uoromethyl-pyridin-2-yl)-l,5-dihydw-pyrwl-2-one. Prepared from 5-(trifluoromethyl)-2-pyridinecarboxyaldehyde, 3-amino-6- methylpyridazine and 2-hydroxy-4-(4-isopropyl-phenyl)-4-oxo-but-2-enoic acid ethyl ester in 11% yield.
  • 1 H-NMR (DMSO-d 6 ) ⁇ (ppm) 1.19 (d, 6H); 2.50 (s, 3H);
  • Example 108 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-4-(5-methyl-pyridine-2- carbonyl)-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 109 3-hydroxy-4-(4-isopropoxy-benzoyl)-5-(4-isopropoxy-phenyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 110 5-(6-ethoxy-pyridin-3-yl)-3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 111 3-Hydroxy-4-(4-isopropyl-benzoyl)-5-(5-isopropyl-pyridin-2-yl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 112 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-4-(6-methyl-pyridine-3- carbonyl)-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 113 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(5- methyl-thiazol-2-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 114 5-(5-ethyl-pyridin-2-yl)-3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 115 3-hydroxy-4-(4-isopropoxy-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5- (4-trifluoromethoxy-phenyl)-l, 5-dihydro-pyrrol-2-one.
  • Example 117 3-hydwxy-4-(6-methoxy-pyridine-3-carbonyl)-l-(6-methyl- pyridazin-3-yl)-5-(4-trifluowmethoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 118 l-(6-chloro-pyridazin-3-yl)-3-hydroxy-4-(4-isopropyl-benzoyl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 120 5-(4-cyclopropoxy-phenyl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 122 5-(5-ethoxy-pyridin-2-yl)-3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 123 4-(4-tert-butyl-benzoyl)-3-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 124 5-(4-acetyl-phenyl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 126 3-hydwxy-l-(6-methyl-pyridazin-3-yl)-5-(4-trifluowmethoxy- phenyl)-4-(6-trifluoromethyl-pyridine-3-carbonyl)-l,5-dihydro-pyrrol-2-one.
  • Example 127 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5- pyridin-4-yl-l, 5-dihydro-pyrrol-2-one.
  • Example 128 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(5-methyl-pyrazin-2-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 130 3-[3-hydroxy-4-(4-isopropyl-benzoyl)-2-oxo-5-(4-trifluoromethoxy- phenyl)-2,5-dihydro-pyrrol-l-yl]-l-methyl-lH-pyridin-2-one.
  • Example 131 3-hydroxy-4-(4-isobutyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 132 3-hydwxy-4-(4-isopwpyl-benzoyl)-5-(4-methanesulfonyl-phenyl)-l- (6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 133 4-[4-hydroxy-3-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)- 5-oxo-2,5-dihydro-lH-pyrrol-2-yl]-benzonitrile.
  • Example 134 5-(4-fluoro-phenyl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 135 5-(4-dimethylamino-phenyl)-3-hydwxy-4-(4-isopwpyl-benzoyl)-l- (6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 137 5-(4-ethynyl-phenyl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)- 1 ,5-dihydro-pyrrol-2-one.
  • Example 141 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- fl,2,4Jtriazol-l-ylmethyl-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 142 3-hydroxy-4-(4-isopropenyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5- (4-trifluoromethoxy-phenyl)-l, 5-dihydro-pyrrol-2-one.
  • Example 144 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- fl,2,4Jtriazol-l-yl-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 145 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- pyrazol-l-ylmethyl-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 146 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- [l,2,3]triazol-l-ylmethyl-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 148 3-hydwxy-5-(4-imidazol-l-ylmethyl-phenyl)-4-(4-isopwpyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one .
  • Example 150 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-
  • Example 151 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-(4-tetrazol-2-ylmethyl- phenyl)-4-(4-trifluoromethoxy-benzoyl)-l,5-dihydro-pyrrol-2-one.
  • Example 153 3-hydwxy-l-(6-methyl-pyridazin-3-yl)-5-(4-[l,2,3]triazol-2- ylmethyl-phenyl)-4-(4-tri ⁇ uoromethoxy-benzoyl)-l,5-dihydw-pyrwl-2-one.
  • Example 154 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-(4-tetrazol-l-ylmethyl- phenyl)-4-(4-tri ⁇ uowmethoxy-benzoyl)-l,5-dihydw-pyrwl-2-one.
  • Example 156 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-(4-[l,2,4]triazol-l- ylmethyl-phenyl)-4-(4-trifluoromethoxy-benzoyl)-l,5-dihydro-pyrrol-2-one.
  • Example 157 3-hydwxy-4-(4-isopwpyl-benzoyl)-5-[4-(l-methyl-lH-pyrazol-3-yl)- phenyl]-l-(6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • 1 H-NMR (DMSO-d 6 ) ⁇ (ppm) 1.18 (d, 6H); 2.50 (s, 3H);
  • Example 158 5-[4-(l,l-difluoro-ethyl)-phenyl]-3-hydroxy-4-(4-isopropyl-benzoyl)- l-(6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 160 3-hydwxy-5-(4-isopwpenyl-phenyl)-4-(4-isopwpyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 161 l-(6-benzyloxy-pyridazin-3-yl)-3-hydroxy-4-(4-isopropyl-benzoyl)-5-
  • Example 162 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-(4-trifluoromethoxy- phenyl)-4-(4-trifluoromethyl-benzoyl)-l,5-dihydro-pyrrol-2-one.
  • Example 163 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-[4- (2H-tetrazol-5-yl)-phenylJ-l,5-dihydw-pyrwl-2-one.
  • Example 165 3-hydroxy-5-(6-isopropoxy-pyridin-3-yl)-4-(4-isopropyl-benzoyl)-l- (6-methyl-pyridazin-3-yl)-l, 5-dihydro-pyrrol-2-one.
  • Example 168 3-hydwxy-l-(6-methyl-pyridazin-3-yl)-5-[4-(2H-tetrazol-5-yl)- phenylJ-4-(4-tri ⁇ uowmethoxy-benzoyl)-l,5-dihydw-pyrwl-2-one.
  • Example 170 5-[4-(l-benzyl-lH-tetrazol-5-yloxy)-phenyl]-3-hydroxy-4-(4- isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 172 5-(4-bromo-phenyl)-3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l, 5-dihydw-pyrwl-2-one. Prepared from 4-bromobenzaldehyde, 3-amino-6-methylpyridazine and 2-hydroxy-4- (4-isopropyl-phenyl)-4-oxo-but-2-enoic acid ethyl ester in 30% yield.
  • Example 174 5-[4-(l,l-difluoro-ethoxy)-phenyl]-3-hydroxy-4-(4-isopropyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 175 4-[2-[4-(l,l-difluow-ethyl)-phenyl]-4-hydwxy-l-(6-methyl- pyridazin-3-yl)-5-oxo-2,5-dihydro-lH-pyrrole-3-carbonyl]-benzonitrile.
  • Example 176 4-[4-hydroxy-l-(6-methyl-pyridazin-3-yl)-5-oxo-2-(4- tri ⁇ uoromethoxy-phenyl)-2,5-dihydw-lH-pyrwle-3-carbonylJ-benzonitrile.
  • Example 177 3-hydroxy-4-(4-methanesulfonyl-benzoyl)-l-(6-methyl-pyridazin-3- yl)-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one
  • Example 178 5-[4-(l,l-difluoro-ethyl)-phenyl]-3-hydroxy-4-(4-isopropyl-benzoyl)- l-(5-methyl-pyrimidin-2-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 179 5-(6-dimethylamino-pyridin-3-yl)-3-hydroxy-4-(4-isopropyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 180 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(5-methyl-pyrimidin-2-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 183 5-[4-(l,l-difluow-ethoxy)-phenyl]-3-hydwxy-l-(6-methyl-pyridazin- 3-yl)-4-(4-pyrrolidin-l-yl-benzoyl)-l,5-dihydw-pyrwl-2-one.
  • Example 184 3-hydroxy-l-(6-methyl-pyridazin-3-yl)-4-(4-pyrrolidin-l-yl-benzoyl)- 5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one
  • Example 185 3-hydroxy-4-(4-isopropyl-benzoyl)-5-[4-(5-methyl-isoxazol-3-yloxy)- phenyl]-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 187 5-[6-(l,l-difluoro-ethyl)-pyridin-3-yl]-3-hydwxy-4-(4-isopwpyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • 6-(l,l-difluoro-ethyl)-pyridine-3-carbaldehyde 3-amino-6- methylpyridazine and 2-hydroxy-4-(4-isopropyl-phenyl)-4-oxo-but-2-enoic acid ethyl ester in 22% yield.
  • Example 200 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5- ⁇ 4- [l-(2-trimethylsilanyl-ethoxymethyl)-lH-[l,2,4]triazol-3-yloxy]-phenyl ⁇ -l,5- dihydro-pyrrol-2-one.
  • Example 53 3-hydroxy-5-(4-isopropyl-phenyl)-4-(methoxyimino-p-tolyl-methyl)-l- (6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one. Prepared from 3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)- 1 -(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one ⁇ Example 8) and methylhydroxylamine hydrochloride as E/Z mixture in 30% yield.
  • Example 54 3-hydwxy-4-(hydwxyimino-p-tolyl-methyl)-5-(4-isopwpyl-phenyl)-l- (6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 55 [l-[4-Hydroxy-2-(4-isopropyl-phenyl)-l-(6-methyl-pyridazin-3-yl)-5- oxo-2,5-dihydro-lH-pyrrol-3-yl]-l-(4-isopropyl-phenyl)-meth-ylideneaminooxy]- acetic acid.
  • Example 83 [[4-Hydroxy-l-(6-methyl-pyridazin-3-yl)-5-oxo-2-(4- trifluoromethoxy-phenyl)-2,5-dihydro-lH-pyrrol-3-yl]-(4-isopropyl-phenyl)- methyleneaminooxy] -acetic acid.
  • Example 84 3-Hydroxy-4- ⁇ (4-isopropyl-phenyl)-[2-methoxy-ethoxyimino]- methyl ⁇ -l-(6-methyl-pyridazin-3-yl)-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro- pyrrol-2-one.
  • Example 56 Acetic acid 4-(4-isopropyl-benzoyl)-5-(4-isopropyl-phenyl)-l-(6- methyl-pyridazin-3-yl)-2-oxo-2, 5-hydw-lH-pyrwl-3-yl ester.
  • Example 76 Acetic acid 4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5- (4-trifluoromethoxy-phenyl)-2, 5-dihydro-lH-pyrrol-3-yl ester.
  • Example 86 Acetic acid 4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2- oxo-5-(4-trifluowmethoxy-phenyl)-2,5-dihydw-lH-pyrwl-3-yl ester.
  • Example 186 Isobutyric acid 4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)- 2-oxo-5-(4-tri ⁇ uoromethoxy-phenyl)-2,5-dihydro-lH-pyrrol-3-yl ester.
  • Procedure F preparation of intermediate Intermediate 7: 4-[4-(2-dimethylamino-ethyl)-piperazin-l-yl]-benzaldehyde.
  • Example 66 5-[3-hydroxy-4-(4-isopropyl-benzoyl)-5-(4-isopropyl-phenyl)-2-oxo- 2, 5-dihydro-pyrrol-l-yl]-2-methyl-pyridinium; chloride.
  • Example 155 2-ethoxy-5-[4-hydroxy-3-(4-isopropyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-5-oxo-2,5-dihydro-lH-pyrrol-2-yl]-pyridinium; chloride.
  • Example 167 3-hydroxy-5-(6-isopropoxy-pyridin-3-yl)-4-(4-isopropyl-benzoyl)- l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one; hydrochloride.
  • Example 67 Sodium; 4-(4-isopropyl-benzoyl)-5-(4-isopropyl-phenyl)-l-(6-methyl- pyridin-3-yl)-2-oxo-2,5-dihydro-lH-pyrrol-3-olate. Prepared from 3-hydroxy-4-(4-isopropyl-benzoyl)-5-(4-isopropyl-phenyl)- 1 -(6- methyl-pyridin-3-yl)-l,5-dihydro-pyrrol-2-one ⁇ Example 48) in quantitative yield.
  • Example 74 3-amino-4-(4-isopwpyl-benzoyl)-5-(4-isopwpyl-phenyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Example 75 3-amino-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- tri ⁇ uoromethoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • the diastereoisomers formation is an adapted procedure from Zou et al. Letters in Drug Design & Discovery, 2007, 4, 185-191.
  • Rl, R2 and R3 are as defined above.
  • Example 201 (R)-[4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5(R)- (4-trifluoromethoxy-phenyl)-2, S-dihydw-lH-pyrwlS-yloxyJ-phenyl-acetic acid methyl ester (Diastereoisomer A).
  • Example 203 (R)-[4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5(S)- (4-tri ⁇ uowmethyl-phenyl)-2,5-dihydw-lH-pyrwl-3-yloxyJ-phenyl-acetic acid methyl ester (diastereoisomer B).
  • Example 204 (R)-[4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5(R)- (4-tri ⁇ uoromethyl-phenyl)-2,5-dihydro-lH-pyrrol-3-yloxyJ-phenyl-acetic acid methyl ester (diastereoisomer A).
  • Example 205 (R)-[5(R)-(6-ethoxy-pyridin-3-yl)-4-(4-isopropyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-2-oxo-2,5-dihydro-lH-pyrrol-3-yloxy]-phenyl-acetic acid methyl ester (diastereoisomer A).
  • Example 206 (R)-[5(S)-(6-ethoxy-pyridin-3-yl)-4-(4-isopropyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-2-oxo-2,5-dihydro-lH-pyrrol-3-yloxy]-phenyl-acetic acid methyl ester (diastereoisomer B).
  • Example 207 (R)-[4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5(S)- (6-trifluoromethyl-pyridin-3-yl)-2,5-dihydro-lH-pyrrol-3-yloxy]-phenyl-acetic acid methyl ester (diastereoisomer B).
  • Example 208 (R)-[4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5(R)- (6-trifluoromethyl-pyridin-3-yl)-2,5-dihydro-lH-pyrrol-3-yloxy]-phenyl-acetic acid methyl ester (diastereoisomer A).
  • Example 211 (R)-[4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5(R)- (4-tri ⁇ uoromethoxy-phenyl)-2, 5-d ⁇ hydro-lH-pyrrol-3-yloxy]-phenyl-acetic acid methyl ester (diastereoisomer A).
  • Diastereoisomer A was dissolved in methanol (10ml / mmol) and ethyl acetate (5ml/mmol).
  • Diastereoisomer B was dissolved in dichloromethane (16ml / mmol) and methanol (l lml/mmol). Each solution was purged under argon and the palladium on actived charcoal (10 %) was added. Each reaction mixture was stirred, independently, at atmospheric pressure in a hydrogen atmosphere for 16h at room temperature. After filtration of the mixture on Celite®, the solid was washed with CH 2 Cl 2 / MeOH (50/50) and the filtrate was concentrated under vacuum. Then, the residue was triturated in Et 2 O and after filtration the solid was washed with Et 2 O to give the corresponding enantiomer.
  • Example 188 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5(R)- (4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 189 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5(S)- (4-tri ⁇ uowmethoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Example 190 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5(S)- (4-trifluoromethyl-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 191 3-hydroxy-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5(R)- (4-trifluoromethyl-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 192 5(R)-(6-ethoxy-pyridin-3-yl)-3-hydroxy-4-(4-isopropyl-benzoyl)-l- (6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one
  • Example 193 5(S)-(6-ethoxy-pyridin-3-yl)-3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6- methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one
  • Example 195 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5(R)- (6-tri ⁇ uowmethyl-pyridin-3-yl)-l,5-dihydw-pyrwl-2-one.
  • Example 196 5(R)-[4-(l,l-difluoro-ethyl)-phenyl]-3-hydroxy-4-(4-isopropyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one
  • Example 197 5(S)-[4-(l,l-difluoro-ethyl)-phenyl]-3-hydroxy-4-(4-isopropyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one
  • Step 2 Prepared from (R)-[5(S)-[4-(l,l-difluoro-ethyl)-phenyl]-4-(4-isopropyl- benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-2,5-dihydro-lH-pyrrol-3-yloxy]-phenyl- acetic acid methyl ester ⁇ Example 210, diastereoisomer B) in 29% yield.
  • Example 198 N-[4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5(R)- (4-trifluowmethoxy-phenyl)-2,5-dihydw-lH-pyrwl-3-yl]-methanesulfonamide.
  • Example 91 3-methoxy-4-(4-methyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 92 5-(4-isopropyl-phenyl)-3-methoxy-4-(4-methyl-benzoyl)-l-(6-methyl- pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one.
  • Trimethylsilyl-diazomethane (solution 2N in hexane, 1.2eq) was added at room temperature to a solution of 3-hydroxy-5-(4-isopropyl-phenyl)-4-(4-methyl-benzoyl)- l-(6-methyl-pyridazin-3-yl)-l,5-dihydro-pyrrol-2-one (Example 8) (leq) in dichloromethane (4ml/mmol) and methanol (4ml/mmol). The reaction mixture was stirred at room temperature for 5h and concentrated under vacuum. The residue was purified by flash chromatography (silica gel) with the appropriate gradient determined by TLC to give the desired compound in 61% yield.
  • Example 119 3-hydroxy-4-(4-isopropyl-benzoyl)-l-[6-(4-nitro-phenylsulfanyl)- pyridazin-3-yl]-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 138 3-chlow-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5-(4- tri ⁇ uoromethoxy-phenyl)-l,5-dihydw-pyrwl-2-one.
  • Oxalyl chloride 6.03 mmol (3eq) was added at 0 0 C to a solution of example 61 (leq) in dry dichloromethane and dry DMF (20ml/20ml). The mixture was stirred 4h at 0 0 C, then diluted with NaHCO 3 10% and extracted twice with ethyl acetate. The combined organic layer was washed with H 2 O then dried on anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography (silica gel) to give the titled compound, in 29% yield.
  • Example 149 N-[4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-2-oxo-5-(4- trifluoromethoxy-phenyl)-2,5-dihydw-lH-pyrwl-3-yl]-methanesulfonamide.
  • Sodium hydride (1.08 mmol, 1.2eq) was added portionwise to a solution of the methane sulphonamide (1.2eq) in dry DMF (10ml) and under nitrogen. The mixture was stirred at room temperature for 30min and Example 138 (leq) in dry DMF (10ml) was added.
  • Example 171 3-Isopropylamino-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3- yl)-5-(4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Example 182 3-hydwxy-4-(4-isopwpyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5- ⁇ 4- [l-(2-trimethylsilanyl-ethoxymethyl)-lH-[l,2,4]triazol-3-yloxy]-phenyl ⁇ -l,5- dihydw-pyrwl-2-one.
  • Example 212 3-chloro-4-(4-isopropyl-benzoyl)-l-(6-methyl-pyridazin-3-yl)-5(R)- (4-trifluoromethoxy-phenyl)-l,5-dihydro-pyrrol-2-one.
  • Oxalyl chloride 6.03 mmol (3eq) was added at 0 0 C to a solution of example 188 (leq) in dry dichloromethane and dry DMF (20ml/20ml). The mixture was stirred 4h at 0 0 C, then diluted with NaHCO 3 10% and extracted twice with ethyl acetate. The combined organic layer was washed with H 2 O then dried on anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography (silica gel) to give the titled compound, in 41% yield.
  • Human Hepatoma Huh-7 cell line was maintained in DMEM/HAMF-12 supplemented with 10% SVF, 4 mM glutamine, 0.5M Na pyruvate, 1% penistreptomycine.
  • HCV replicon containing Huh-7 cell lines Huh-9.13 and Luc Neo ET (Reblikon) were maintained in DMEM supplemented with 10% SVF, 2 mM glutamine, and 1 X NEAA, 100 U / ml penicillin, and 100 ⁇ g / ml strep tomy cine.
  • Replicon cells were maintained in medium supplemented with 1 mg/ml G418 for replicon Huh-9.13 and 0.5 mg/ml for Luc Neo et replicon unless indicated otherwise.
  • Huh-7 and HCV replicon cell lines were maintained at 37°C and 5% CO 2 in a humidified atmosphere. Cells were dissociated at sub confluence with trypsin EDTA IX.
  • cDNA encoding HCV NS5B genotype Ib was cloned in frame with GaW-DNA Binding Domain. The protein was expressed with a 21 amino acid C-terminal deletion to remove transmembrane domain. Expression of NS5B ⁇ 21/Gal4DBD fusion protein was under control of SV40 early promoter. 3D-Sensor peptide was cloned in frame with VP 16 activation domain. Expression of 3D-Sensor / VP 16 AD fusion protein was under control of CMV promoter. Expression of the firefly luciferase reporter gene was inducible by the [Target protein / conformation sensitive peptide / VP 16AD] complex.
  • 3D-SCREEN assay is a reporter gene assay designed to identify chemical entities that modify the 3D-structure of target proteins and hence inhibit their biological activity (WO2006/046134). It is a single-target, cell based assay. Briefly, expression of a reporter gene depends on the interaction of a short peptide, thereafter named 3D- Sensor, and native conformation of the target protein. Whenever the conformation of the target protein is modified, interaction between 3D-sensor and target protein is disrupted and reporter gene is not expressed anymore. Conformation modifiers are identified by loss of expression of reporter gene.
  • NS5B 3D-Screen platform was generated in Huh-7 cell lines by transient transfection of three expression vectors encoding respectively
  • Huh-7 cells were dissociated the day before transfection and seeded in T 175 flasks at a density of 10 7 cells in 30 ml culture medium. Equimolar ratios of vectors were transfected in cell according to optimized jetPEI transfection protocol (PolyPlus Transfection, Illkirch, France) and 10 ⁇ g total DNA / 10 6 cells. Transfection was performed for 2 hours at 37°C and 5% CO 2 in a humidified atmosphere. After two hours cells were dissociated and seeded in 96 wells plates at a density of 25,000 cells per well and 90 ⁇ l culture medium. 10 ⁇ l of compounds to be tested were added 2 hours after seeding. Final concentration of DMSO was 1%.
  • Cells were incubated in the presence of compounds for 24 hours after which expression of firefly luciferase reporter gene was quantified. Briefly, culture medium was removed and cells were lysed by addition of 100 ⁇ l of lysis buffer containing 125 mM Tris Phosphate ph 7.8, 10 mM EDTA, 5 mM DTT, 50 % glycerol and 5 % Triton. Plates were vortexed 10 min at 1300 rpm. Cell Iy sat was transferred in Opaque White Assay 96 well Flat Bottom plates. lOO ⁇ l of luciferin solution IX were added to each well.
  • Luciferin solution contained 40 mM Tris Phosphate ph 7.8, 0.2 mM EDTA, 67 mM DTT, 2.14 mM MgC12, 5.4 mM MgSO4, 4.7 x 10 "4 M luciferin, 5.3 x 10 "4 M ATP and 2.7 x 10 "4 M Acetyl co enzyme A.
  • Replicon Luc Neo ET is a bicistronic expression constructs (Lohmann et al, 1999, Science 285, 110-113).
  • the structural genes of the HCV genome were replaced by heterologous sequences; the gene encoding the neomycin phosphotransferase (NPT) and the internal ribosome entry site (IRES) of the encephalomyocarditis virus (EMCV).
  • the bicistronic construct is therefore composed of the following elements: HCV-IRES nucleotides 1-389, the NPT gene, the EMCV-IRES directing translation of downstream HCV sequences from NS2 or NS3 up to the authentic 3' end of the genome.
  • HCV Polyprotein harbours the cell culture adaptive mutations E1202G, T1280I, K1846T. G418-resistance is only possible with cells containing high amounts of replicon.
  • Cells were dissociated the day before addition of compounds and seeded in 96 well- plates at a final concentration of 77 111.11 cells.mr'.weir 2 in 90 ⁇ l final volume of culture medium per well and were maintained at 37°C and 5% CO 2 in a humidified atmosphere for 24 hours. 10 ⁇ l of compounds to be tested were added 24 hours after seeding. Final concentration of DMSO was 1%. Cells were incubated in the presence of compounds for 72 hours after which expression of firefly luciferase reporter gene was quantified.
  • culture medium was removed and cells were lysed by addition of 100 ⁇ l of lysis buffer containing 125 mM Tris Phosphate ph 7.8, 10 mM EDTA, 5 mM DTT, 50 % glycerol and 5 % Triton. Plates were vortexed 10 min at 1300 rpm. Cell lysat was transferred in Opaque White Assay 96 well Flat Bottom plates. lOO ⁇ l of luciferin solution IX were added to each well.
  • Luciferin solution contained 40 mM Tris Phosphate ph 7.8, 0.2 mM EDTA, 67 mM DTT, 2.14 mM MgC12, 5.4 mM MgSO4, 4.7 x 10 "4 M luciferin, 5.3 x 10 "4 M ATP and 2.7 x 10 "4 M Acetyl co enzyme A.
  • Luminescence was immediately measured with Berthold Microlumat Plus LB 96V luminometer with an integration of 0.5 sec. Inhibition was calculated using the formula:
  • % inhibition l-[(RLUsample-RLUbackground)/(RLUsignal-RLUbackground)] HCV NS5B RdRp enzyme assay
  • the assay was performed in a total volume of 20 ⁇ l containing 20 mM Tris pH 7.5, 1 mM DTT, 17 U RNasin, 50 mM NaCl, 10% DMSO, 5 mM MgCl 2 , 0.5 mM each of the 3 NTPs (ATP, CTP, GTP), 86 nM RNA template (341 nt from the 3'end of HCV minus strand RNA), 50 nM of purified HCV NS5B with a deletion of the 21 C- terminal amino acids and 2 ⁇ Ci [ 3 H]UTP (46 Ci.mmol "1 ).
  • the reaction mixture was incubated for 2 h at 25-30 0 C and the radiolabeled products were precipitated by the addition of 10% TCA.
  • the radioactivity incorporated was quantified by counting in a Wallac scintillation counter. Increasing concentrations of tested compounds were added to the complete RdRp reaction mixture. After a two hour incubation period at 25-30 0 C, the amount of labeled product was determined as above.
  • Two types of control reactions were done: a negative control corresponding to the complete mixture without enzyme and a positive control with enzyme but without compounds. In each experiment, test and control samples are in duplicate.
  • % activity (test tube) 3 H cpm test tube - 3 H cpm negative control
  • the IC50 value was calculated as the compound concentration reducing polymerase activity by 50%.
  • Example 63 50% inhibition at 10 ⁇ M
  • hepatitis C virus RNA-dependent RNA polymerase membrane insertion sequence is a transmembrane segment. J Virol. 2002 Dec;76(24): 13088-93.

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Abstract

La présente invention concerne un composé 1-(azo-hétérocycle à 6 chaînons)-pyrrolin-2-one de formule I ou l'un de ses sels, solvats, tautomères, isotopes, énantiomères, diastéréo-isomères ou mélanges racémiques, sa composition pharmaceutique et son utilisation thérapeutique comme inhibiteurs de polymérase NS5B d'hépatite C.
PCT/EP2010/059917 2009-07-10 2010-07-09 Composés 1-(azo-hétérocycle à 6 chaînons)-pyrrolin-2-one comme inhibiteurs de polymérase ns5b d'hépatite c, leur composition pharmaceutique et leur utilisation thérapeutique Ceased WO2011004017A1 (fr)

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US20120128630A1 (en) 2012-05-24
EP2451800A1 (fr) 2012-05-16
AU2010270152A1 (en) 2012-02-02
JP2012532849A (ja) 2012-12-20
CA2767467A1 (fr) 2011-01-13

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